Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2.
Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2.
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DOI：
10.1371/journal.pone.0005933
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发表时间：
2009-06-16
期刊：
影响因子：
3.7
通讯作者：
Kim TY
中科院分区：
文献类型：
--
作者：
Kim HP;Yoon YK;Kim JW;Han SW;Hur HS;Park J;Lee JH;Oh DY;Im SA;Bang YJ;Kim TY
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）已被证明与氟嘧啶联合使用时可发挥协同抗肿瘤作用。这种协同作用可能归因于胸苷酸合酶（TS）的下调，该酶在氟嘧啶耐药癌细胞中经常过度表达。然而，TS下调的分子机制尚未明确阐明。在这项研究中，我们证明拉帕替尼（EGFR 和 HER2 的双重 TKI）通过抑制 EGFR 和 HER2 的核易位来下调 TS。从我们的 cDNA 微阵列实验中，我们确定拉帕替尼下调了多种核苷酸合成相关基因（包括 TS），这在 HER2 扩增细胞中很明显。靶向和药理学抑制测定证实，与单独使用吉非替尼或曲妥珠单抗观察到的结果相比，需要对 EGFR 和 HER2 进行双重抑制才能更有效地降低 TS。此外，我们确定共转染的 EGFR 和 HER2 比单独的 EGFR 或 HER2 更能有效地激活 TS 基因启动子。拉帕替尼抑制 EGFR 和 HER2 转位至细胞核以及随后 TS 启动子的激活。这些结果表明，拉帕替尼抑制 EGFR 和 HER2 的核转位并下调 TS，从而使癌细胞对氟嘧啶敏感。
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been shown to exert a synergistic antitumor effect when combined with fluoropyrimidine. This synergy may be attributable to the downregulation of thymidylate synthase (TS), which is frequently overexpressed in fluoropyrimidine-resistant cancer cells. However, the molecular mechanism underlying the downregulation of TS has yet to be clearly elucidated. In this study, we demonstrate that lapatinib, a dual TKI of EGFR and HER2 downregulates TS via inhibition of the nuclear translocation of EGFR and HER2. From our cDNA microarray experiments, we determined that a variety of nucleotide synthesis-related genes, including TS, were downregulated with lapatinib, and this was apparent in HER2-amplified cells. Targeted and pharmacologic inhibition assays confirmed that the dual inhibition of EGFR and HER2 is required for the more effective reduction of TS as compared to what was observed with gefitinib or trasutuzumab alone. Additionally, we determined that co-transfected EGFR and HER2 activate the TS gene promoter more profoundly than do either EGFR or HER2 alone. The translocation of EGFR and HER2 into the nucleus and the subsequent activation of the TS promoter were inhibited by lapatinib. These results demonstrate that lapatinib inhibits the nuclear translocation of EGFR and HER2 and downregulates TS, thus sensitizing cancer cells to fluoropyrimidine.
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